Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) are typical examples of a major health problem for which the efficacy of treatment is limited once the condition is fully established. Enormous basic and clinical research efforts have lead to improvements in supportive treatment, but surprisingly little research has been done into prevention of this devastating syndrome. Delayed recognition of patients at risk for ALI/ARDS until after admission to the ICU has limited clinical trials to enrolling patients with already established disease, beyond the therapeutic window of potential prevention strategies. Our recently described novel system for identification of patients at high risk before the development of respiratory failure and the full blown syndrome (LIPS - Lung Injury Prediction Score) and the standardized approach to important aspects of critical care delivery (CLIP - Checklist for Lung Injury Prevention) have laid the groundwork for developing rational strategies to limit or even prevent this life-threatening syndrome. Increasing evidence supports the critical role of anti-inflammatory lipid mediators, platelets and platelet- neutrophil interactions in the development of ALI and the ability of aspirin (ASA) to effectively prevent the development and progression of this syndrome. Our preliminary data has identified an independent association between ASA therapy and decreased development of ALI in three large cohorts of at risk patients, making this simple intervention an ideal target of a formal, phase II ALI prevention trial. A multidisciplinary team of clinical investigators from fourteen academic medical centers who have joined together in the US Critical Illness and Injury Trials Network LIPS-A study group will utilize the established infrastructure for clinical research in the emergency and critical care setting to address critical knowledge gaps by a) determining the efficacy of ASA for prevention of ALI in patients at high risk identified early in the course of their illness, b) evaluating the mechanisms by which platelet activation and its inhibition affect ALI development, and c) assess the value of lung injury biomarkers as prognostic markers of ALI development in patients at risk in order to optimize the design and conduct of future ALI prevention trials. The better understanding of ALI risk, and the efficacy and safety of potential prevention strategies, are essential steps for further progress in limiting the impact of this devastating complication of critical illness. RELEVANCE (See instructions): Each year ALI accounts for 3.5 million hospital days and 75,000 deaths in the USA. Survivors frequently incur long-term decrease in quality of life and enormous costs related to intensive care and rehabilitation. Therefore, ALI represents a major public health problem and effective prevention of ALI will have a major impact on outcomes of critically ill and injured patients and associated healthcare cost. (End of Abstract)